A characteristic of the autoimmune disease systemic lupus erythematosus is the appearance of antibodies to DNA. This is also true for (NZB x NZW) F1 mice, an experimental model for lupus. Anti-DNA antibodies can be induced in both mice and humans with non-specific polyclonal B cell activators. However, only autoimmune mice and individuals with lupus generate a sustained anti-DNA antibody response. Moreover, only autoimmune mice and humans with lupus produce IgG anti-DNA antibodies. Although IgM anti-DNA antibodies in autoimmune mice have the characteristics of a non-specifically induced, polyclonal population of antibodies, recent evidence suggests that the IgG anti-DNA antibodies may be clonally restricted. The experiments outline herein are designed to analyze the clonal diversity of both IgM and IgG anti-DNA antibodies in autoimmune (NZB x NZw) F1 mice. They are also designed to determine whether IgG anti-DNA antibodies are related to the earlier appearing IgM anti-DNA antibodies within an individual autoimmune mouse. Moreover, these experiments will determine whether IgG anti-DNA antibody-producing B cells are clonally selected from earlier appearing IgM anti-DNA antibody- producing B cells. These experiments will determine whether changes in DNA binding accompany the IgM to IgG switch among anti- DNA antibodies. Finally, these experiments will determine whether somatic mutation of immunoglobulin variable region genes accompany the isotype switch. Hopefully the results from these experiments will provide new insight into the processes that operate to generate antibodies to DNA in autoimmune mice and in humans with lupus.